According to WHO estimates there are clearly more than 20 million people infected by HIV-1 or HIV-2. Sooner or later that infection manifests itself by way of preliminary stages, such as ARDS, in a manifest disease of the immune system which is known as "Acquired Immunodeficiency Syndrome" or AIDS. In the overwhelming number of cases the disease sooner or later leads to the death of the infected patients.
Hitherto, the treatment of retroviral diseases, such as AIDS, has involved principally the use of inhibitors of reverse transcriptase, an enzyme effective in the conversion of retroviral RNA into DNA, such as 3'-azido-3'-deoxythymidine (AZT) or dideoxyinosine (DDI), and also trisodium phosphonoformate, ammonium-21-tungstenato-9-antimonate, 1-.beta.-D-ribofuranoxyl-1,2,4-triazole-3-carboxamide and dideoxycytidine and also adriamycin. Attempts have also been made to introduce into the body, for example in the form of a recombinant molecule or molecule fragment, the T4-cell receptor which is present in certain cells of the defence system of the human body and is responsible for the anchoring and introduction of infectious virus particles into those cells and thus for their infection, the objective being that binding sites for the virus will be blocked so that the virions will no longer be able to bind to the cells. Compounds that prevent the virus penetrating the cell membrane in some other way, such as polymannoacetate, are also used.
Also reported are advanced clinical experiments with a hydroxyethylene isostere as an inhibitor of HIV-protease, N-tert-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-2-quinolyl-carbon yl-L-asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide (Ro 31-8959). That compound exhibits an inhibitory action against HIV-protease in vitro, suppression of virus replication in cell experiments and, in experiments on rodents, blood levels that are still usable are achieved even in the case of oral administration (see Roberts, N. A., et al., Biochemical Soc. Transactions 20, 513-516 (1992)); usable blood levels have also been achieved in humans (see e.g. G. J. Muirhead et al., Brit. J. Clin. Pharmacol. 34, 170P-171 P (1992)). A so-called "surrogate-marker" (titre of the CD4-lymphocytes in the blood, the decrease in which in untreated patients is a measure of the advance of the AIDS disease) has shown initial positive effects in AIDS patients (see "Roche Statement on HIV Proteinase Inhibitor (Ro 31-8959) European Trials Results", distributed to participants in the 9th International Congress on AIDS in Berlin, Jun. 7-11, 1993). A disadvantage of that compound, Ro 31-8959, is that it is expensive to synthesise.
Also under development are a number of further inhibitors of retroviral aspartate protease, an enzyme the function of which can be characterised as follows:
In the AIDS viruses, HIV-1 and HIV-2, and other retroviruses, for example corresponding viruses in cats (FIV) and apes (SIV), the proteolytic maturation of, for example, the core proteins of the virus is brought about by an aspartate protease, such as HIV-protease. Without that proteolytic maturation, infectious virus particles cannot be formed. Owing to the central role of the said aspartate proteases, such as HIV-1- or HIV-2-protease, in the maturation of viruses and on the basis of experimental results, for example on infected cell cultures, it has become plausible that effective suppression of the maturation step brought about by that protease will suppress the assembly of mature virions in vivo. Corresponding inhibitors can therefore be used therapeutically.
The aim of the present invention is to provide a novel type of compound that is equipped, especially, with a high degree of inhibitory activity against virus replication in cells, high anti-viral activity against numerous virus strains, including those which are resistant to known compounds, such as saquinavir and indinavir, and especially advantageous pharmacological properties, for example good pharmacokinetics, such as high bioavailabilty and high blood levels, and/or high selectivity.